Unsaturated alcohols having an ether protected group

ABSTRACT

A synthesis of 2,6,10-trimethyl-undecan-1-ol, an intermediate for producing vitamin E, from methacrolein, crotonaldehyde, β-hydroxy-isobutyric acid including intermediates in this synthesis.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a division of application Ser. No. 796,929, filed May 16, 1977,and now U.S. Pat. No. 4,107,183, which is a divisional application ofSer. No. 638,722, filed Dec. 8, 1975 and now U.S. Pat. No. 4,041.058,which is a continuation-in-part of Ser. No. 544,154, filed Jan. 27, 1975and now abandoned.

This application is related to U.S. patent application Ser. No. 417,465,filed Nov. 19, 1973, Scott, Parrish and Saucy, which is incorporatedherein by reference.

BACKGROUND OF THE INVENTION

In the past, optically active α-tocopherol and derivatives thereof whichare the 2R,4'R, 8'R isomers of compounds of the formula: ##STR1## havebeen prepared through isolation from natural sources such as vegetableoil. This procedure suffers from many drawbacks due to the fact that thetocopherol content of these oils is very small. Therefore, a greatamount of oil must be processed in order to isolate a small amount ofnatural tocopherol. Additionally, the process whereby varioustocopherols are isolated from vegetable oil is extremely cumbersome.

In U.S. patent application Ser. No. 417,465, filed Nov. 19, 1973, Scottet al., vitamin E active compounds have been synthesized by reacting viaa Wittig reaction a compound of the formula: ##STR2## wherein R ishydrogen or forms an ether protecting group removable by hydrogenolysisor acid catalyzed cleavage.

(Please note, the compound of the formula XXVII where n is 1 in U.S.patent application Ser. No. 417,465, filed Nov. 19, 1973) with aphosphonium salt prepared from a compound of the formula: ##STR3##(Please note, compound XLIV in U.S. patent application Ser. No. 417,465filed Nov. 19, 1973). Where the compound of the formula III has a 2R, 6Rconfiguration, i.e. a compound of the formula: ##STR4## then naturalα-tocopherol is produced by this procedure.

In accordance with this process, it has been desired to provide a simpleand economic method for preparing the compound of formula III and III-Afrom relatively cheap and economic starting materials.

SUMMARY OF THE INVENTION

In accordance with this invention, the compound of formula III can beprepared from either methacrolein which has the formula: ##STR5## orβ-hydroxy isobutyric acid which has the formula: ##STR6## In accordancewith this invention, the compound of formula III can be produced in anydesired configurations such as the following stereoconfigurations:

2R, 6R;

2RS, 6RS;

2R, 6RS; and

2RS, 6R.

depending on the optical configuration of the compound of formula IV-B.

This invention also provides a direct means for asymmetricallysynthesizing the specific stereoisomer of formula III-A and consequentlyoptically active vitamin E directly from the aforementioned startingmaterials without the loss of yield due to the production of an unwantedisomer.

DETAILED DESCRIPTION OF THE INVENTION

The numbering of the chains in formula I, III and III-A, above, is shownfor the purpose of convenience.

As used throughout this application, the term "lower alkyl" comprehendsboth straight and branched chain saturated hydrocarbon groups containingfrom 1 to 7 carbon atoms such as methyl, ethyl, propyl, isopropyl, etc.As used throughout this application, the term "halogen" includes allfour halogens, such as bromine, chlorine, fluorine and iodine. The term"alkali metal" includes sodium, potassium, lithium, etc.

When the term "cis" is utilized in this application, it designates thatthe two largest substituents attached across the double bond are on thesame side of the double bond. The term "trans" as utilized in thisapplication, designates that the largest substituents attached acrossthe double bond are on opposite sides of the double bond.

In the pictorial representation of the compounds given throughout thisapplication, a ( ) tapered line indicates a substituent which is pointedout of the plane of the paper towards the reader.

The term "lower alkoxy" as used through the specification denotes loweralkoxy groups containing from 1 to 7 carbon atoms such as methoxy,ethoxy, propoxy, isopropoxy, etc. The term "lower alkanoyl" as usedthroughout this specification denotes lower alkanoyl groups containingfrom 2 to 5 carbon atoms such as acetyl or propionyl.

As also used herein, the term "aryl" signifies mononuclear aromatichydrocarbon groups such as phenyl, tolyl, etc. which can beunsubstituted or substituted in one or more positions with a loweralkylenedioxy, a halogen, a nitro, a lower alkoxy or a lower alkoxysubstituent, and polynuclear aryl groups such as naphthyl, anthryl,phenanthryl, azulyl, etc., which can be unsubstituted or substitutedwith one or more of the aforementioned groups. The preferred aryl groupsare the substituted and unsubstituted mononuclear aryl groups,particularly phenyl. The term "aryl lower alkyl" comprehends groupswherein aryl and lower alkyl are as defined above, particularly benzyl.The term "aroic acid" comprehends acids wherein the aryl group isdefined above. The preferred aroic acid is benzoic acid.

As still further used herein, the term "ester protecting group removableby hydrolysis" comprehends any conventional organic acid protectinggroup which can be removed by hydrolysis. The preferred organic acidprotecting groups are the esters. Any conventional ester that can behydrolyzed to yield the acid can be utilized as the protecting group.Exemplary esters useful for this purpose are the lower alkyl esters,particularly methyl, tertiary butyl and ethyl ester, the aryl esters,particularly phenyl ester and the aryl lower alkyl esters, particularlybenzyl ester. The alcohols utilized to form the hydrolyzable esterprotecting group are lower alkanols or an aryl lower alkanols orreactive derivatives thereof. Among the reactive derivatives which canbe utilized to form such ester groups are the alkyl halides, preferablythe chlorides or the bromides.

The term "ether protecting group removable by hydrogenolysis or acidcatalyzed cleavage" designates any ether which, upon acid catalyzedcleavage or hydrogenolysis yields the hydroxy group. A suitable etherprotecting group is, for example, the tetrahydropyranyl ether or4-methyl-5,6-dihydro-2H-pyranyl ether. Others are arylmethyl ethers suchas benzyl, benzylhydryl, or trityl ethers or alpha-lower alkoxy loweralkyl ether, for example, methoxymethyl or allylic ethers, or triarylethers such as trimethyl silyl ether or dimethyl-tert-butyl silylethers.

The preferred ethers which are removed by acid catalyzed cleavage aret-butyl and tetrahydropyranyl. Acid catalyzed cleavage is carried out bytreatment with a strong organic or inorganic acid. Among the preferredinorganic acids are the mineral acids such as sulfuric acid, hydrohalicacid, etc. Among the preferred organic acids are lower alkanoic acidssuch as acetic acid, paratoluene sulfonic acid, etc. The acid catalyzedcleavage can be carried out in an aqueous medium or in an organicsolvent medium. Where an organic acid is utilized, the organic acid canbe the solvent medium. In the case of t-butyl, an organic acid isgenerally utilized with the acid forming the solvent medium. In the caseof tetrahydropyranyl ethers, the cleavage is generally carried out in anaqueous medium. In carrying out this reaction, temperature and pressureare not critical and this reaction can be carried out at roomtemperature and atmospheric pressure.

The preferred ethers which are removable by hydrogenolysis are the arylmethyl ethers such as benzyl or substituted benzyl ethers. Thehydrogenolysis can be carried out by hydrogenation in the presence of asuitable hydrogenation catalyst. Any conventional method ofhydrogenation can be utilized in carrying out this procedure. Anyconventional hydrogenation catalyst such as palladium can be utilized.

In accordance with this invention, the compound of formula IV-A can beconverted to the compound of the formula III via the followingintermediates: ##STR7## wherein R₁ is aryl;

R₂ is hydrogen, lower alkoxy, ##STR8## R'₂ is lower alkoxy and R₃, R₄and R₅ are lower alkyl.

In the first step of this invention, methacrolein is reacted with analcohol of the formula:

    R.sub.1 CH.sub.2 OH                                        XIII

wherein R₁ is as above;

to produce the compound of formula V. In this reaction, theaforementioned alcohol is reacted with methacrolein in the presence ofan inorganic base. Any conventional inorganic base such as an alkalimetal hydroxide can be utilized to carry out this reaction. Among thepreferred alkali metal hydroxides are included sodium hydroxide andpotassium hydroxide. Generally this reaction is carried out in anaqueous medium. In carrying out this reaction, temperature and pressureare not critical and this reaction can be carried out at roomtemperature and atmospheric pressure. On the other hand, elevated orreduced temperatures can be utilized. Generally, it is preferred tocarry out this reaction at a temperature of between -25° C. to +20° C.

The compound of formula V is converted to the compound of formula VI bytreating the compound of formula V with an alkali metal borohydridereducing agent. The temperature and pressure are not critical and thisreaction can be carried out at room temperature and atmosphericpressure. In carrying out this reaction, any conventional alkali metalborohydride reducing agent such as sodium borohydride can be utilized.This reaction is carried out under the same conditions of temperatureand pressure that were utilized to form the compound of formula V.Furthermore, this reaction is carried out in an aqueous medium. On theother hand, the methacrolein and the aforementioned alcohol can bedirectly reacted in the aqueous medium with sodium hydroxide and analkali metal borohydride reducing agent to produce the compound offormula VI directly without isolating the compound of formula V from thereaction medium. In this case, the same temperatures and pressurespreviously described for the formation of the compound of formula VIfrom the compound of formula V can be utilized.

The compound of formula VI is converted to the compound of formula VIIby treating the compound of formula VI with a halogenating agent. Any ofthe conditions conventional in halogenating an alcohol can be utilizedto carry out this reaction. Among the conventional methods ofhalogenating the compound of formula VI is by treating compounds offormula VI with a halogenating agent. Among the conventionalhalogenating agents which can be utilized are included phosphoroustribromide, triphenyl phosphine dibromide and thionyl chloride. Any ofthe conditions conventional in utilizing these halogenating agents canbe utilized to convert the compound of formula VI to the compound offormula VII.

In accordance with another embodiment of this invention, the compound offormula VI can be prepared in an alternate procedure from a compound ofthe formula ##STR9## via the following intermediates: ##STR10## whereinR₁ and R₄ are as above.

The compound of formula XV is reacted with the compound of formula XIIIto produce the compound of XV-A utilizing a conjugate addition reaction.Any of the conditions conventional in conjugate additions can beutilized in carrying out this reaction. Generally, this reaction iscarried out utilizing the compound of formula XIII as the solvent mediumand an alkali metal hydride. In carrying out this reaction temperatureand pressure are not critical and this reaction can be carried out atroom temperature and atmospheric pressure. Generally this reaction iscarried out at a temperature of from 30° C. to 90° C. The compound offormula XV-A is converted to the compound of the formula XV-B bytreating the compound of the formula XV-A with an inorganic acid.Generally this reaction is carried out in a lower alkanol solvent, suchas methanol, ethanol, propanyl, etc. In carrying out this reaction, anyconventional inert organic acid such as hydrohalic acids, sulfuric acid,etc. can be utilized. It is generally preferred to treat the compound ofthe formula XV-A with a lower alkanol solvent which is saturated with aninorganic acid, i.e., methanol saturated with hydrochloric acid. Incarrying out this reaction, temperatures of from -30° C. to 65° C. canbe utilized.

The compound of formula XV-B is converted to the compound of formula VI,via this alternative method of producing the compound of formula VI, bytreatment with an aluminum hydride reducing agent. Any conventionalaluminum hydride reducing agent can be utilized to carry out thisreaction. Among the preferred reducing agents are the alkali metalaluminum hydrides such as lithium aluminum hydride, the alkyl aluminumhydride reducing agents such as diisobutyl aluminum hydride, diisoamylaluminum hydride, as well as sodiumdihydro-bis-[2-methoxyethoxy]-aluminum hydride. The reduction with analuminum hydride reducing agent is carried out in an inert organicsolvent medium. Any conventional inert organic solvent medium can beutilized as the reaction medium. Among the preferred inert organicsolvents are included pentane, tetrahydrofuran, dioxane, diethyl ether,hexane, toluene, benzene or xylene. Generally temperatures of from about-120° C. to about 30° C. are utilized in carrying out this reductionreaction.

The compound of formula VII is converted to the compound of formula VIIIvia a Grignard reaction. In this reaction, the magnesium halide Grignardreagent of formula VII is prepared. This Grignard reagent is preparedutilizing the conventional procedures for forming magnesium halideGrignard reagents. This Grignard reagent of formula VII is then reactedwith crotonaldehyde via a conventional Grignard reaction. In carryingout this reaction, any of the conditions conventionally utilized inGrignard reactions can be used. The Grignard rection produces a transdouble bond within the molecule of formula VIII.

In an alternative approach, the compound of formula VIII can be producedfrom the compound of formula VII via the following intermediates:##STR11##

In this alternative synthesis of the compound of formula VIII, thecompound of formula VII, is first treated with an alkali metal cyanide.In this manner, the compound of formula XVI is formed. This reaction iscarried out by conventional procedures utilizing an aqueous loweralkanol solvent as the reaction medium. In carrying out this reaction,temperatures of from 50° C. to 100° C. are generally utilized. In thenext step, the compounds of formula XVI is converted to the compound offormula XVII by treatment with diisobutyl aluminum hydride. Any of theconditions normally used to reduce nitriles to imines with diisobutylaluminum hydride can be utilized in carrying out this reaction. Thecompound of formula XVII is converted to the compound of formula XXVIIIby acid hydrolysis. Any conventional method of acid hydrolysis can beutilized to carry out this conversion. Generally this hydrolysisreaction is carried out in an aqueous medium with an inorganic acid suchas sulfuric acid, hydrochloric acid, etc. In this reaction, temperatureand pressure are not critical and the hydrolysis can be carried out atroom temperature or atmospheric pressure. On the other hand, elevated orreduced temperatures and pressures can be utilized in carrying out thisreaction.

The compound of formula XVIII is converted to the compound of formulaXIX, in the next step of this alternative synthesis, by treating thecompound of formula XVIII with an alkali metal acetylide of the formula:

    CH.sub.3 --C.tbd.CM                                        XX

wherein M is an alkali metal.

In carrying out this reaction, any of the conventional procedures forreacting acetylides with aldehydes to form addition products can beutilized. In the final step of this alternative procedure, the compoundof formula XIX can be converted by either one of two methods to thecompound of formula VIII. These methods are either hydrogenation in thepresence of a selective hydrogenation catalyst or chemical reductionwith either sodium in liquid ammonia or an aluminum hydride reducingagent. The catalytic hydrogenation produces a compound of the formulaVIII where the double bond formed has a cis configuration. On the otherhand, chemical reduction of the compound of formula XIX produces thecompound of formula VIII where the double bond formed by this chemicalreduction has a trans configuration.

The compound of formula XIX is converted to the compound of the formulaVIII by hydrogenation in the presence of a selective hydrogenationcatalyst. Any conventional catalyst which selectively reduces only thetriple bond (acetylene linkage) to a double bond can be utilized incarrying out this conversion. Among the preferred selectivehydrogenation catalysts are the palladium catalysts which contain adeactivating material such as lead, lead oxide or sulfur. Among thepreferred selective hydrogenation catalysts are included thepalladium-lead catalyst of the type disclosed in Helvetica ChimicaActa., 35, pg. 446 (1952) and U.S. Pat. No. 2,681,938 - Lindlar. Incarrying out this hydrogenation, temperature is not critical and thisreaction can be carried out at room temperature. On the other hand,elevated or reduced temperatures can be utilized. Generally, thisreaction is carried out in an inert organic solvent. Any conventionalinert organic solvent can be utilized such as ethyl acetate, toluene,petroleum ether or hexane. The hydrogenation of a compound of theformula XIX utilizing a selective hydrogenation catalyst produces a cisconfiguration across the double bond formed thereby. Therefore, thesubjection of a compound of the formula XIX to catalytic hydrogenationproduces a compound of the formula VIII where the double bond formed bythe selective hydrogenation has a cis configuration.

In accordance with this invention, the compound of formula XIX can alsobe converted to the compound of formula VIII by chemical reduction witheither sodium in liquid ammonia or an aluminum hydride reducing agent.The chemical reduction of the compound of the formula XIX reduces thetriple bond to a double bond which has a trans configuration. Hence, thecompound of formula VIII is formed by this chemical reduction with thedouble bond having a trans configuration. Where the reduction is carriedout utilizing sodium in liquid ammonia, any of the conditionsconventional in this type of reduction can be utilized. Generally, thisreaction is carried out at a temperature of from about -30° C. to -80°C. In this reduction, the liquid ammonia can be utilized as the reactionmedium. On the other hand, a co-solvent can be present in the reactionmedium along with liquid ammonia. As the co-solvent, any conventionalinert organic solvent which is in liquid form at the temperature of thereaction can be utilized. Among the preferred inert organic solvents areincluded ether solvents such as dioxane, diethyl ether, tetrahydrofuran,etc. On the other hand, the reduction can be carried out by treating thecompound of formula XIX with an aluminum hydride reducing agent. Anyconventional aluminum hydride reducing agent can be utilized to carryout this reduction. Among the preferred reducing agents are the alkalimetal aluminum hydrides such as sodiumdihydrobis[2-methoxyethoxy]aluminum hydride. The reduction with analuminum hydride reducing agent is carried out in an inert organicsolvent medium. Any conventional inert organic solvent medium can beutilized for carrying out this reaction. Among the preferred inertorganic solvents are included pentane, dioxane, diethyl ether,tetrahydrofuran, hexane, toluene, benzene or xylene. Generally,temperatures of from about -120° C. to about 30° C. are utilized incarrying out this reduction reaction.

In accordance with this invention, when the compound of formula VIII issubjected to Claisen rearrangement, the compound of formula IX isproduced via the formation of a compound of the formula: ##STR12##wherein R₁ is as above; R₈ is hydrogen, lower alkoxy, ##STR13## and R₃,R₄ and R₅ are lower alkyl; as an intermediate.

Any of the conditions conventional in Claisen rearrangement can beutilized in carrying out the conversion of the compound of the formulaVIII to form a compound of the formula IX. See Hill et al., J. Org.Chem., Vol. 37, No. 32, 1972, pages 3737-3740, as well as Sucrow et al.,Che. Ber., 104, 3689-3709 [1971], and Sucrow and Richter, Chem. Ber.,104, 3679-3688 [1971].

The compound of formula VIII is converted, via the Claisen reaction, tothe compound of formula IX via the intermediate of the formula IX-A. Incarrying out this reaction, any of the conditions conventionallyutilized in Claisen type rearrangement reactions such as described inthe above publications can be utilized. In accordance with the preferredembodiment of this invention, the Claisen rearrangement is carried outby reacting the compounds of formula VIII with any one of the followingreactants: ##STR14## wherein R₃, R₄ and R₅ are as above, and R₁₀ islower alkyl, and X is halogen.

The compound of formula IX where R₂ is hydrogen can be formed byreacting the compound of formula VIII with the vinyl ether of formulaXX-A via a Claisen rearrangement reaction. Any of the conditionsconventional in carrying out a Claisen rearrangement with a vinyl ethercan be utilized in carrying out this reaction. Where the compound offormula XX-A is utilized, the compound of formula IX-A where R₈ ishydrogen is formed as an intermediate. In converting the compound offormula VIII to the compound of formula IX, the compound of formula VIIIis first reacted with the vinyl ether of formula XX-A. In reacting thecompound of formula VIII with the compound of formula XX-A to form thecompound of formula IX-A where R₈ is hydrogen, temperatures of fromabout 40° C. to 150° C. are generally utilized. This reaction takesplace in the presence of an acid catalyst. Any conventional acidcatalyst can be utilized. Among the preferred acid catalysts are theinorganic acids such as phosphoric acid and the hydrohalic acids as wellas acid salts such as mercuric acetate. On the other hand, conventionalorganic acid catalysts such as p-toluene sulfonic acid and p-nitrophenolcan be utilized. This reaction can be carried out in an inert organicsolvent. Any conventional inert organic solvent having a boiling pointof greater than 40° C. can be utilized. Among the preferred solvents arethe high boiling hydrocarbon solvents such as benzene, toluene, xylene,heptane, as well as ether solvents such as dimethoxyethane, diethyleneglycol, dimethyl ether and dioxane. The compound of formula IX-A whereR₈ is hydrogen is converted to the compound of formula IX where R₂ ishydrogen by heating to a temperature of from 80° C. to 200° C. Thisreaction is carried out in the absence of any catalyst. However, thesame solvent medium utilized for forming the compound of the formulaIX-A can be utilized in carrying out this reaction.

On the other hand, the compound of the formula VIII can be converted tothe compound of formula IX where R₂ is lower alkoxy utilizingorthoacetates of formula XX-B. In carrying out this reaction, any of theconditions conventionally utilized in Claisen rearrangements with anorthoacetate can be utilized. In this reaction, the compound of formulaIX-A where R₈ is lower alkoxy forms as an intermediate. Under thecondition of the reaction, the compound of formula IX-A where R₈ islower alkoxy rearranges to produce the compound of formula IX where R₂is lower alkoxy. In carrying out this reaction, temperatures of from140° C. to 250° C. are generally utilized. This reaction is carried outin the presence of excess of the orthoacetate of formula XX-B. This istrue since the orthoacetate can be utilized as the solvent medium. Onthe other hand, the reaction can take place in an inert organic solvent.Generally those solvents having a boiling point of greater than 140° C.are preferred. Generally, it is preferred to carry out this reaction inthe presence of a lower alkanoic acid. If desired, the lower alkanoicacid is present in molar amounts of from 1% to 10% per mole of thecompound of the formula VIII.

Where it is desired to produce the compound of formula IX where R₂ is##STR15## the compound of formula VIII is first converted to a compoundof the formula: ##STR16## by acylation with acetic acid or a reactivederivative thereof. Any conventional method of acylating a hydroxy groupwith an acetyl group can be utilized to carry out this conversion. Amongthe preferred methods is to react the compound of formula VIII with areactive derivative of an acetic acid such as a halide derivative or ananhydride derivative. In the next step, the compound of formula VIII-Ais converted to its enolate form, i.e., compound of the formula:##STR17## wherein M is as above; by treatment with an alkali metal alkylamide base. Any conventional alkali metal alkyl amide base can beutilized. The alkyl moiety can be a lower alkyl or cycloalkyl moietywhich contains from 5 to 7 carbon atoms. Among the preferred bases arelithium cyclohexylisopropyl amide and lithium diisopropylamide.

The enolate of formula VIII-B are then reacted with the silyl halide ofthe formula XX-E to form the compound of the formula IX via a Claisenreaction. In this reaction, the compound of the formula IX-A is formed,where R₈ is ##STR18## as an intermediate. This reaction to produce thecompound of formula IX-A takes place in an inert organic solvent mediumat temperatures of from -10° C. to -110° C. In carrying out thisreaction, any conventional inert organic solvent which will not freezeat the reaction temperature can be utilized. Among the preferredsolvents are tetrahydrofuran, diethyl ether, dioxane anddimethoxyethane.

The compound of the formula IX-A where R₈ is ##STR19## is converted tothe corresponding compound of the formula IX by warming this compound inthe reaction medium in which it was formed to a temperature of from 0°C. to 40° C. Therefore, in accordance with this invention, there is noneed to isolate the compound of formula IX-A from the reaction mixture.The reaction mixture containing the compound of formula IX-A can bewarmed to a temperature of from 0° C. to 40° C. to form the compound ofthe formula IX. The compound of formula IX-A can, if desired, beisolated from the reaction mixture before warming.

Where it is desired to produce the compound of formula IX where R₂ is##STR20## the compound of formula VIII is reacted with a compound offormula XX-C or formula XX-D or mixtures thereof utilizing conditionsconventional in Claisen reactions with amides. In this reaction, thecompounds of the formula IX-A where R₈ is ##STR21## forms as anintermediate. This intermediate is instantaneously converted to thecompound of formula IX under the conditions of the reaction. Thisreaction is carried out at tempertures of from 120° C. to 250° C. in aninert organic solvent. Any conventional inert organic solvent can beutilized to carry out this reaction with high boiling solvents, i.e.,solvents being above 150° C. being preferably utilized. Among theconventional inert organic solvents are included xylene and diglyme.

Where R₂ in the compound of formula IX is other than hydrogen or loweralkoxy, the compound of formula IX can be converted to the compound offormula X by first hydrolyzing the silyl ester or amide group and thenesterifying the free hydroxy group with a lower alkanol or reactivederivatives thereof. Any conventional method of silyl ester or amidehydrolysis and esterification can be utilized to affect this conversion.On the other hand, the compound of formula IX where R₂ is lower alkoxyis the compound of formula X. Where R₂ is hydrogen, in the compound offormula IX, this compound is the compound of formula XII.

The compound of formula X is converted to the compound of the formula XIby reduction with an aluminum hydride reducing agent. This reaction iscarried out in the same manner as described in connection with theconversion of a compound of the formula XV-B to the compound of theformula VI. The compound of the formula XI is converted to the compoundof the formula XII by treating the compound of the formula XI with anoxidizing agent, capable of converting an alcohol to an aldehyde. Any ofthe conventional oxidizing agents for converting alcohols to aldehydescan be utilized in this process. The preferred oxidizing agents for usein this type of conversion is a chromium trioxide-pyridine complex.Generally, this preferred oxidation is carried out in a halogenatedhydrocarbon solvents such as chloroform, methylene chloride, etc. Incarrying out this reaction, temperature and pressure are not criticaland this reaction can be carried out at room temperature and atmosphericpressure. On the other hand, elevated temperatures as well as reducedtemperatures can be utilized in carrying out this oxidation.

The compound of formula XII is converted to the compound of formula XIVby reacting the compound of formula XII with a phosphorane of theformula: ##STR22## wherein R₁₂, R₁₃ and R₁₄ are aryl. This reaction iscarried out by a conventional Wittig type reaction. Any of theconditions conventional in Wittig type reactions can be utilized toconvert the compound of formula XII to the compound of formula XIV.

The compound of formula XIV is converted to the compound of formula IIIby hydrogenation. Any conventional method of hydrogenation can beutilized to carry out this reaction. Generally, it is preferred to carryout this reaction by hydrogenating the compound of formula XIV in thepresence of a noble metal catalyst such as palladium. While palladium ispreferred, any conventional noble metal catalyst can be utilized tocarry out this reaction. Any of the common supports for noble metalcatalysts can be utilized in accordance with this invention. Among thepreferred catalyst supports for use in this invention are supports suchas carbon, charcoal, barium sulfate, etc. In carrying out thishydrogenation reaction, any of the conventional inert organic solventscan be utilized. In carrying out this reaction, temperature and pressureare not critical and this reaction can be carried out at roomtemperature and atmospheric pressure. On the other hand, higher or lowertemperatures can be utilized. This hydrogenation besides reducing thedouble bond also cleaves the ether linkage to form the compound offormula III.

In accordance with another embodiment of this invention, the compound offormula VI where the R₁ CH₂ substituent is replaced by R₁₁, where R₁₁taken together with its attached oxygen atom forms an ether protectinggroup convertable to hydroxy by acid catalyzed cleavage, can be producedfrom beta-hydroxy isobutyric acid via a compound of the formula##STR23## wherein --OR₁₁ forms an ether protecting group convertable tohydroxy by acid catalyzed cleavage; and --OR₁₂ forms an ester protectinggroup convertable to hydroxy by hydrolysis.

In forming the compound of formula XXV, beta-hydroxy isobutyric acid isesterified and etherified so that both its free hydroxy groups areprotected. In this step, the free --CH₂ OH group is etherified to form acleavage ether while the free ##STR24## group is esterified to form ahydrolyzable ester. The cleavable ether and the hydrolyzable ester groupcan be formed separately. On the other hand, the ether and ester may beformed in one step by reacting the hydroxy acid with isobutylene in thepresence of an inorganic acid and boron trifluoride etherate. Thisreaction can be carried out at temperatures such as -100° C. to 30° C.By this reaction, the acid is esterified with a tertiary butyl group andthe hydroxy group is etherified with a tertiary butyl group.

Among the preferred cleavable ether groups are includedtetrahydropyranyl. In forming this ether, any of the conventionalconditions utilized in reacting hydroxy groups with activated alcoholderivatives can be utilized. On the other hand, the acid group ofbeta-hydroxy isobutyric acid can be esterified by reacting the acid withan alcohol. Any of the conditions conventional in forming esters can beutilized to carry out this reaction. Among the preferred esters arethose where the R₁₂ is a lower alkyl group.

The compound of the formula XXV is converted to the compound of formulaVI (where R₁ CH₂ O-- is replaced by --OR₁₁ and R₁₁ is defined as above)by treating the compound of formula XXV with an aluminum hydridereducing agent. Any of the conventional aluminum hydride reducing agentssuch as disclosed in connection with the conversion of a compound of theformula XV-B to a compound of the formula VI can be utilized in thisreaction. Furthermore, any of the conditions described in connectionwith the conversion of a compound of the formula XV-B to a compound ofthe formula VI can also be utilized in this reaction.

Where it is desired to produce the compound of formula III with a 2R or2S configuration, the beta-hydroxy isobutyric acid having the properconfiguration about the asymmetric carbon atom is utilized. Forinstance, where the compound of formula III having a 2R configuration isdesired, the compound of the formula ##STR25## i.e., S-(+)-beta-hydroxyisobutyric acid is utilized as a starting material. The configurationabout this asymmetric atom in the compound of the formula IV-B₁ ismaintained throughout the various intermediates in the conversion to thecompound of formula III.

During the conversion of a compound of formula VI to a compound offormula III, the R₁ CH₂ O-- group in the various intermediates formedduring this conversion is replaced by --OR₁₁ with R₁₁ being defined asabove.

Where R₁ CH₂ O-- is replaced by R₁₁ O-- in the compound of formula XVII,this compound has the formula ##STR26## where R₁₁ is as above. Thecompound of formula XVII-A is converted to the corresponding compound offormula XVIII, i.e., a compound of the formula ##STR27## by acidhydrolysis so as not to cleave the protecting group formed by R₁₁ O.This hydrolysis is carried out in an aqueous medium at a pH of from 4 to5. Any weak acid which provides a pH of from 4 to 5 can be utilized inthis reaction. The preferred weak acid is ammonium chloride. In thisreaction, temperature and pressure are not critical and the hydrolysiscan be carried out at room temperature and atmospheric pressure. Ifdesired, higher and lower temperatures can be utilized.

Where R₁ CHO-- is replaced by R₁₁ O-- in the compound of formula XIV,hydrogenation of this compound produces a compound of the formula##STR28## wherein R₁₁ is as above. The compound of formula XIV-B isconverted to the compound of formula III by acid catalyzed cleavage asdescribed above.

In the compound of formula X wherein R₁ CH₂ O-- is replaced by R₁₁ O--,i.e., the compound of the formula X-A, this compound can be converted inaccordance with one embodiment of this invention, to the compound offormula III via the following intermediates: ##STR29## wherein R₁₁ is asabove and A and B are individually hydrogen or taken together form acarbon to carbon bond.

The compound of formula X-A is converted to the compound of formula IIIin the same manner as described in connection with the conversion of acompound of the formula X to a compound of the formula III. However, inthese reactions the double bond in the compound of formula X-A, can, ifdesired, be reduced by hydrogenation. On the other hand, the double bondformed by A and B can be reduced at anytime during the conversion of thecompound of formula XI-A to the compound of formula III. This reductioncan be carried out by hydrogenation in the manner described inconnection with the conversion of a compound of the formula XIV to acompound of the formula III.

Where it is desired to produce the isomer of formula III-A, the compoundof formula IV-B₁ is utilized as a starting material to produce thecompound of formula XIX which has the following configuration: ##STR30##wherein R₁₁ is as above. The compound of the formula XIX-A can beseparated into its two epimers: ##STR31## wherein R₁₁ is as above bychromatography such as high pressure liquid chromatography. Anyconventional method of high pressure liquid chromatography can beutilized to make this separation. In accordance with this invention, theepimers of the formula XIX-A₁ and XIX-A₂ can be converted to thecompound of formula IX of the following configuration: ##STR32## whereinR₁₁ and R₂ are as above; via the following intermediates: ##STR33##wherein R₈, R₁₁ and M are as above;

Δ denotes a trans configuration and

Δ' denotes a cis configuration.

The compound of formula XIX-A₁ is converted to the compound of theformula XXX-A by chemical reduction with either sodium in liquid ammoniaor an aluminum hydride reducing agent as described in connection withthe conversion of a compound of the formula XIX to the compound of theformula VIII. The chemical reduction produces the compound of formulaXXX-A where the double bond formed by this selective hydrogenation has atrans configuration. On the other hand, the compound of the formulaXIX-A₂ is converted to the compound of the formula XXX-B by catalytichydrogenation with a selective hydrogenation catalyst as described inconnection with the conversion of the compound of the formula XIX to acompound of the formula VIII. This catalytic hydrogenation produces adouble bond with a cis configuration.

Where either the compound of the formula XXX-A or XXX-B is subjected toa Claisen rearrangement via the intermediates of the formula XXXI-A,XXXI-B, XXXII-A, XXXII-B, XXXIII-A and XXXIII-B, the specific opticalisomer of the compound of formula IX-B is produced. In accordance withthe claimed invention, the subjection of either of the compound of theformula XXX-A or XXX-B to Claisen rearrangement produces a singleoptical isomer. In order to achieve this result, it is necessary thatthe compound of formula XXX-A be separated from the compound of formulaXXX-B. Without this separation, the specific isomer of formula IX-B willnot be produced upon Claisen rearrangement. In accordance with thisprocess, the compound of formula IX-B is produced without discarding anyunwanted isomer.

The compounds of XXX-A and XXX-B are both converted to the compound offormula IX-B via a Claisen rearrangement with any one of the reactantsof formula XX-A, XX-B, XX-C, XX-D or XX-E. This reaction is carried outin the same manner as described in connection with the conversion of acompound of the formula VIII to the compound of the formula IX. Where acompound of the formula XXX-A is utilized, the compound of the formulaXXXIII-A forms as an intermediate. On the other hand, where the compoundof the formula XXX-B is utilized in this Claisen rearrangement, thecompound of formula XXXIII-B forms as an intermediate.

In accordance with this invention, it has been discovered that Claisenrearrangement is carried out without any cleavage of the ether group R₁₁O-- even though this ether group is removable by acid catalyzedcleavage. This is completely unexpected since many of the Claisen typereactions are carried out with acids and under conditions which wouldnormally cleave the ether group --OR₁₁. This is extremely advantageoussince the Claisen reaction leaves the hydroxy group protected for futurereactions without the need for a separate reaction step for reprotectingthe hydroxy group so that further reactions can be carried out. Where acompound of formula XX-E is utilized as the rearrangement agent in theClaisen reaction, the compound of formula XXX-A and XXX-B is firstreacted with an acetylating agent to form the compound of formula XXXI-Aand XXXI-B. This acetylation is carried out in the same manner asdescribed hereinbefore in connection with the conversion of a compoundof the formula VIII to a compound of the formula VIII-A. In the nextstep prior to reaction with the rearranging agent of the formula XX-E,the compound of the formula XXXI-A or XXXI-B is converted into itsenolate forms, i.e., the compound of formula XXXII-A and XXXII-Brespectively. These enolate forms are produced in the same manner asdescribed in connection with the compound of the formula VIII-B. It isthese enolates which are then reacted with the compound of the formulaXX-E to form the compound of the formula IX-B. This reaction is carriedout in the same manner as described in connection with the reaction of acompound of the formula XX-E with a compound of the formula VIII-B toform the compound of the formula IX.

The compound of the formula IX-B is converted to the compound of theformula III-A in the same manner as described in connection with theconversion of a compound of the formula IX to a compound of the formulaIII. In the intermediates which form, i.e., the compounds of the formulaX, XI, XII and XIV, the same configuration is maintained about both ofthe asymmetric carbon atoms throughout the conversion and formation ofthese intermediates.

In accordance with another embodiment of this invention, the compound offormula XI or XI-A can be converted to the compound of formula XIV orXIV-A via the condensation of a compound of the formula: ##STR34## witha compound of the formula: ##STR35## wherein A and B are as above; oneof R₂₀ and R₂₁ is --MgX and the other is OR₂₂ ; X is halogen and --OR₂₂is a leaving group; and R'₁₁ forms with its attached oxygen moiety anether protecting group removable by hydrogenolysis or acid catalyzedcleavage; with the proviso that when R'₁₁ forms an ether protectinggroup removable by hydrogenolysis; A and B form a carbon to carbon bond.

The compound of formula XI or XI-A can be converted to the compound offormula XL where --OR₂₀ is a leaving group by utilizing any conventionalmethod of converting a hydroxy group to a leaving group. Among thepreferred methods is to react the compound of formula XIV or XIV-A withan aryl sulfonyl halide as a naphthylsulfonyl halide, p-toluene sulfonylhalide, etc. or a lower alkyl sulfonyl halide, methylsulfonyl halide inthe presence of an organic amine base such as pyridine, trimethyl amine,etc. In accordance with this invention, when R₂₁ O in the compound offormula XLI is --OR₂₂, this compound can be prepared from: ##STR36## inthe same manner as described in connection with the conversion of acompound of the formula XI-A to a compound of the formula XL.

The compound of formula XL, where R₂₀ --MgX can be prepared from thecompound of formula XI or XI-A utilizing any conventional method ofpreparing a Grignard reagent. In the same manner, the compound offormula XLI where R₂₁ is MgX is prepared from the compound of formulaXLI-A.

In the compounds of formulae XL or XLI, --OR₂₂ can be any conventionalleaving group. Among the preferred leaving groups formed by --OR₂₂ arealkyl sulfonyloxy such as methylsulfonyloxy, aryl sulfonyloxy, such asp-toluene-sulfonyloxy, naphthyl-sulfonyloxy, etc.

The compound of formula XL and XLI are reacted to form the compound offormula XIV-A in the presence of a di(alkali metal) tetrahalocuprateutilizing the procedure disclosed by Fouquet and Schlosser on pages 82and 83 of Angew Chem Internat. Edit. Vol. 13 (1974). In the proceduredisclosed by Fouquet and Schlosser, carbon to carbon linkage ofhydrocarbons is carried out through the reaction of a magnesium halidewith a sulfonyl ester. In accordance with this invention, it has beendiscovered that this reaction can be carried out with an etherfunctional group so that either the magnesium halide or sulfonyl estercan carry these functional groups. In accordance with this invention, ithas been discovered that the ether group does not interfere with thereaction. In this reaction, any conventional (di(alkali metal)tetrahalocuprate can be utilized with dilithium tetrachlorocuprate beingpreferred. Generally, this reaction is carried out in the presence of anether solvent. Any conventional inert organic ether solvent can beutilized. Among the preferred solvents are included tetrahydrofuran,dioxane, diethyl ether, dimethoxyethane, diglyme, etc.

Intermediates of the formula VI, VII and XXV due to their fragrance arealso useful as odorants or as additives to odorant compositions. Amongthese intermediates, the following are particularly noted:

A compound of the formula: ##STR37## which has an almond, cinnamon,benzaldehyde and cherry odor;

A compound of the formula: ##STR38## wherein R₁₅ is tertiary butyl;which has a lavendin, fruity, woody odor;

A compound of the formula: ##STR39## wherein R₁₅ is as above; which hasa fruity, rosey odor.

A compound of the formula: ##STR40## wherein R₁₅ is as above; which hasa hay minty, animal, coumarin odor.

A compound of the formula: ##STR41## wherein R₁₅ is as above; which hasa fruity, medicinal, woody odor.

The intermediates of formulae VI, VII and XXV are distinguished by theirparticular odor properties. On the basis they can be used for perfumerypurposes such as manufacture of perfumes or for perfuming products ofall kinds such as cosmetic articles (soaps, powders, creams, lotions,etc.). The content of compounds of formula LIII through LVI in odorantcompositions is governed by the intended use and can vary within widelimits, for example between 0.005-30-wt. percent.

As stated hereinabove, the novel odorant compositions produced inaccordance with the present invention which have excellent odorproperties, may be utilized in a wide range of odor compositionscontaining them. Preferable, however, they are utilized in amountsranging from about 0.5 to about 20% by weight in the compositionscomprising them. And, for example, when utilized for the perfuming ofsoaps, between 1 and 2% by weight of such perfume compositions willsuffice. In compositions such as lotions, suitably hand lotions and thelike, from between 2 to about 3% by weight of such compositions areutilized and in bath salts and essences, depending on the type ofcomposition, between 0.3 and 5% by weight of the composition areutilized.

The following examples are illustrative but not limitative of theinvention. All temperatures are in degrees Centigrade and the ether isdiethyl ether. The 5% palladium designates a catalyst containing 5% byweight palladium on 95% by weight carbon. The term "Lindlar catalyst"designates a catalyst prepared from palladium chloride, calciumcarbonate and lead acetate as described in Organic Synthesis CollectiveVolume 5, page 880-893 (1973). The term "Celite" designates diatomaceousearth.

EXAMPLE 1 Rac. 3-benzyloxy-2-methyl-1-propanol

A solution of 1.59 g. of sodium hydroxide and 1.6 ml. of water in 402ml. (420 g; 3.89 moles) of benzyl alcohol was stirred and cooled to -10°C. while 100 ml. (83.7 g.; 1.19 moles) of freshly distilled methacroleinwere added dropwise keeping the temperature between -10° C. and -5° C.After the reaction mixture had stirred for 0.5 hr. at -10° C., asolution of 44.9 g. (1.19 moles) of sodium borohydride in 180 ml. ofwater was added dropwise over 1.75 hr. keeping the temperature below 5°C. Stirring was continued for an additional hour during which time thereaction mixture was allowed to warm to room temperature. The resultingmixture was poured into ice-water and the organic materials wereextracted several times with ether. The ether extracts were worked up byfirst combining the extracts washing with saturated brine and dryingover anhydrous magnesium sulfate. After filtration and removal of thesolvents in vacuo, the residue was carefully fractionated, giving, afterremoval of low boiling materials, 39.6 g. of rac.3-benzyloxy-2-methyl-1-propanol as a colorless liquid, b.p. 91°-98° C.(0.5 mm Hg.).

EXAMPLE 2 Rac. 3-benzyloxy-2-methyl-1-propyl bromide

A solution of 39 g. (0.216 mole) of rac. 3-benzyloxy-2-methyl-1-propanoland 56.7 g. (0.216 mole) of triphenylphosphine in 216 ml. of drydimethylformamide was stirred while 11.7 ml. (34.4 g.; 0.216 mole) ofbromine was added dropwise, over a 15 min. period, keeping thetemperature below 55° C. A few additional drops of bromine were added,until a yellow color persisted. After cooling to 30° C., the reactionmixture was poured into water and hexane was added. The precipitatedtriphenylphosphine oxide was filtered and washed with hexane. Thefiltrate and washes were combined and separated into aqueous and organicphases. The aqueous phase was extracted once with hexane, then thehexane solutions were combined, washed with 10% by weight aqueous NaHSO₃and brine and dried. The organic solution was filtered and concentratedin vacuo giving 44.2 g. of residue which was distilled under highvacuum. There was obtained 42.3 g. of crude bromide as a colorlessliquid, b.p. 73°- 86° C. (0.05-0.1 mm Hg.). This material was dissolvedin benzene and absorbed on 500 g. of silica gel. Elution with 5.2 l. ofbenzene gave after solvent removal, 38 g. of residue. This material wasdistilled using a Vigreaux column yielding 37.1 g. (70.7%) of pure rac.3-benzyloxy-2-methyl-1-propyl bromide as a colorless liquid, b.p.78°-85° C. (0.05-0.1 mm Hg.).

EXAMPLE 3 rac. E-1-benzyloxy-2-methyl-5-hepten-4-ol

A slurry of 0.55 g. (0.0236 mole) of magnesium powder in 15 ml. ofanhydrous tetrahydrofuran was stirred and heated at reflux while a fewdrops of a solution of 5 g. (0.0206 mole) of rac.3-benzyloxy-2-methyl-1-propyl bromide in 30 ml. of anhydroustetrahydrofuran was added followed by a crystal of iodine. After theGrignard reaction had begun, the remainder of the bromide solution wasadded dropwise over 35 min. at reflux temperature. The reaction mixturewas stirred and heated under reflux for an additional hour then cooledto 0°-5° C. (ice bath) while a solution of 1.56 g. (0.022 mole) ofcrotonaldehyde in 15 ml. of anhydrous tetrahydrofuran was added over a15 min. period. After stirring at room temperature for 2.5 hours, thereaction mixture was poured onto saturated aqueous ammonium chloride andthe product was extracted with ether and worked up as in Example 1. Theresidue (4.62 g.) was chromatographed on 250 g. of silica gel. Elutionwith 4:1 parts by volume and 2:1 parts by volume hexane-ether gave 3.36g. of rac. E-1-benzyloxy-2-methyl-5-hepten-4-ol as a pale yellow oil,b.p. 110°-120° C. (bath temperature) (0.075 mm Hg.).

EXAMPLE 4 rac. Ethyl-8-benzyloxy-3,7-dimethyl-4-octenoate

A solution of 1.1 g (4.7 mmoles) of rac.E-1-benzyloxy-2-methyl-5-hepten-4-ol and 34.8 mg. (0.47 mmole) ofpropionic acid in 5.3 g. (32.9 mmoles) of triethyl orthoacetate wasstirred and heated in an oil bath until distillation began. Distillationwas continued until the internal temperature reached 150° C. then thesolution was maintained at reflux for 3.25 hours. After cooling, thereaction mixture was treated with water and the product was isolatedwith ether and worked up as described in Example 1 (the ether extractswere additionally washed with aqueous sodium bicarbonate solution). Thecrude product was evaporatively distilled giving 1.29 g. (87.5%) of rac.ethyl 8-benzyloxy-3,7-dimethyl-4-octenoate as a pale yellow oil, b.p.123°-132° C. (bath temperature) (0.075 mm Hg.).

EXAMPLE 5 rac. 4-Benzyloxy-3-methylbutyronitrile

A solution of 3.38 g. (0.069 mole) of sodium cyanide and 8.4 g. (0.0345mole) of rac. 3-benzyloxy-2-methyl-1-propyl bromide in 11.5 ml. of waterand 45 ml. of ethanol was stirred and heated at reflux for 20 hours. Thereaction mixture was cooled, diluted with water and the product wasisolated by extraction with benzene and worked up as in Example 1. Thisafforded 6.4 g. of oily residue which was chromatographed on 350 g. ofsilica gel. Elution with 4:1 parts by volume and 2:1 parts by volumehexane:ether gave 5.8 g. (89%) of pure rac.4-benzyloxy-3-methylbutyronitrile as a yellow oil.

EXAMPLE 6 rac. 4-Benzyloxy-3-methylbutanal

A solution of 5.8 g. (0.0307 mole) of rac.4-benzyloxy-3-methylbutyronitrile in 290 ml. of hexane was stirred at-65° C. to -70° C. while 22.4 ml. (4.78 g.; 0.0337 mole) of 25%diisobutylaluminum hydride solution in toluene was added dropwise. Theresulting solution was stirred at -65° C. to -70° C. for 0.5 hours thenat room temperature for 5 hours whereupon 2.8 ml. of ethyl formate wasadded dropwise. The reaction mixture was then treated with 250 ml. ofsaturated aqueous ammonium chloride solution. Stirring was continued for20 minutes at which point 125 ml. of 5% by weight aqueous sulfuric acidwas added and stirring was continued for an additional 10 minutes. Theorganic layer was separated and the aqueous layer was extracted withether. The organic solutions were combined and processed as in Example 1giving 4.79 g. (81.3%) of rac. 4-benzyloxy-3-methylbutanal as a yellowoil.

EXAMPLE 7 rac. 1-Benzyloxy-2-methylhept-5-yn-4-ol

A mixture of 72.8 ml. (0.146 mole) of 2 M n-butyllithium solution inhexane and 420 ml. of anhydrous tetrahydrofuran was stirred and cooledto -50° C. while 112 ml. of liquified methylacetylene was added dropwisefrom a dry ice cooled addition funnel. After the addition was complete,the reaction mixture was allowed to warm to reflux temperature (8° C.)(dry ice condenser) and stirred at this temperature for 1 hour. Thewhite slurry was then cooled to 0° C. and stirred while a solution of 14g. (0.0728 mole) of rac. 4-benzyloxy-3-methylbutanal in 125 ml. ofanhydrous tetrahydrofuran was added dropwise. After stirring at 0° C.for 1 hour, the mixture was slowly warmed to 40° C. and stirred at thistemperature for 1 hour whereupon the reaction mixture was treated withsaturated aqueous ammonium chloride. The product was isolated by etherextraction and worked up as in Example 1. There was obtained 15.4 g. ofcrude material which was chromatographed on 400 g. of silica gel.Elution with 2:1 parts by volume and 1:1 parts by volume hexane:etherafforded rac. 1-benzyloxy-2-methylhept-5-yn-4-ol as a yellow oil.

EXAMPLE 8 rac. Z-1-Benzyloxy-2-methyl-5-hepten-4-ol

A mixture of 1 g. (4.31 mmoles) of rac.1-benzyloxy-2-methylhept-5-yn-4-ol, 0.1 g. of Lindlar catalyst, 0.04 ml.of quinoline and 30 ml. of hexane was stirred in an atmosphere ofhydrogen, at room temperature, for 40 minutes during which timeapproximately one equivalent of hydrogen was taken up. The catalyst wasfiltered and washed with hexane then the combined filtrate and washeswere concentrated in vacuo giving 1.05 g. of oily product. This materialwas chromatographed on 50 g. of silica gel. Elution with 2:1 parts byvolume and 1:1 parts by volume hexane-ether afforded 0.844 g. of a paleyellow oil. Evaporative distillation gave rac.Z-1-benzyloxy-2-methyl-5-hepten-4-ol as a colorless oil, b.p. 113°-123°C. (bath temperature (0.25 mm Hg.).

EXAMPLE 9 rac. E-8-Benzyloxy-3,7-dimethyl-4-octen-1-ol

A suspension of 0.432 g. (11.36 mmoles) of lithium aluminum hydride in20 ml. of anhydrous ether was stirred with ice bath cooling while asolution of 1.73 g. (5.68 mmoles) of rac. ethyl8-benzyloxy-3,7-dimethyl-4-octenoate in 20 ml. of anhydrous ether wasadded over a 25 minute period keeping the temperature at 0°-5° C. Thecooling bath was removed and the reaction mixture was stirred at roomtemperature for 2.5 hours at the end of which time 1.6 ml. of saturatedsodium sulfate solution was cautiously added with ice bath cooling.After stirring for 16 hours at room temperature, the slurry was filteredon Celite and the filter cake was washed thoroughly with ether.Concentration in vacuo of the combined filtrate and washes yielded 1.46g. of a colorless oil. This material was chromatographed on 50 g. ofsilica gel. Elution with 2:1 parts by volume, 1:1 parts by volume and1:2 parts by volume hexane-ether afforded 1.38 g. of rac.E-8-benzyloxy-3,7-dimethyl-4-octen-1-ol which was evaporativelydistilled giving 1.37 g. (92%) of colorless oil, b.p. 107°-108° C. (bathtemperature) (0.03 mm Hg.).

EXAMPLE 10 rac. E-8-Benzyloxy-3,7-dimethyl-4-octenal

To a solution of 1.19 g. of pyridine in 15 ml. of dichloromethane wasadded 0.6 g. (6 mmoles) of chromium trioxide. The brown mixture wasstirred at room temperature for 15 minutes, then treated with a solutionof rac. E-8-benzyloxy-3,7-dimethyl-4-octen-1-ol (0.262 g.; 1 mmole) in 3ml. of dichloromethane. After stirring at room temperature for 15minutes, the dichloromethane solution was decanted from the dark tarryresidue then the residue was washed three times with freshdichloromethane. The dichloromethane solutions were combined and washedwith 1 N aqueous sodium hydroxide, 1 N aqueous hydrochloric acid,saturated aqueous sodium bicarbonate solution and brine then dried,filtered and concentrated in vacuo. The residue (0.255 g.) waschromatographed on 10 g. of silica gel. Elution with 9:1 parts by volumeand 4:1 parts by volume hexane-ether gave 0.196 g. (75.5%) of pure rac.E-8-benzyloxy-3,7-dimethyl-4-octenal. Evaporative distillation yielded acolorless liquid, b.p. 90° -93° C. (bath temperature) (0.1 mm Hg.).

EXAMPLE 11 rac. Benzyl 2,6,10-trimethylundeca-4,8-dien-1-yl ether

A suspension of 1.52 g. (3.42 mmoles) of isobutyltriphenylphosphoniumiodide in 30 ml. of anhydrous tetrahydrofuran was stirred and cooled to0° C. while 1.55 ml. (3.42 mmoles) of n-butyllithium solution in hexanewas added. The resulting red solution was stirred for 10 minutes at roomtemperature then treated with a solution of rac.E-8-benzyloxy-3,7-dimethyl-4-octenal (0.594 g.; 2.28 mmoles) in 10 ml.of anhydrous tetrahydrofuran. After stirring at room temperature for 30minutes, the reaction mixture was treated with water and worked up byextraction with hexane as in Example 1. The semi-solid residue wastreated with hexane and filtered to remove insoluble material. Thefiltrate was concentrated in vacuo to give 0.72 g. of yellow oil. Thismaterial was chromatographed on 30 g. of silica gel. Elution with 9:1parts by volume hexane-ether afforded 0.427 g. (62.5%) of an oil.Evaporative distillation yielded rac. benzyl2,6,10-trimethyl-undeca-4,8-dien-1-yl ether as a colorless liquid, b.p.110°-115° C. (bath temperature) (0.03 mm Hg.).

EXAMPLE 12 rac. 2,6,10-trimethylundecan-1-ol

A mixture of 0.15 g. (0.5 mmole) of rac. benzyl2,6,10-trimethylundeca-4,8-dien-1-yl ether, 0.1 g. of 5% by weightpalladium on 95% by weight carbon and 10 ml. of ethyl acetate wasstirred in an atmosphere of hydrogen for 16 hours at room temperature.The catalyst was filtered and the filtrate was concentrated in vacuo.The oily residue was dissolved in 10 ml. of ethyl acetate andrehydrogenated over 0.1 g. of 5% palladium on carbon, for 5 hours atroom temperature. The catalyst was again filtered and the filtrate wasconcentrated in vacuo. The residue was evaporatively distilled giving0.092 g. (86%) of rac. 2,6,10-trimethylundecan-1-ol as a colorless oil,b.p. 100°-105° C. (bath temperature) (0.02 mm Hg.).

EXAMPLE 13 S-(+)-tert. Butyl 3-tert. butoxy-2-methylpropionate

A mixture of 40 ml. of liquid isobutylene, 0.91 ml. of 100% phosphoricacid (prepared by dissolving 5 g. of phosphorous pentoxide in 11 ml. of85% phosphoric acid) and 2 ml. of boron trifluoride etherate wasprepared at -70° C. to -75° C. and stirred at this temperature while asolution of 5 g. of a mixture of S-(+)-β-hydroxyisobutyric acid (˜38% byg c analysis) and isobutyric acid (˜55% by g c analysis) in 75 ml. ofdichloromethane was added over a 5 minute period. The reaction mixturewas stirred at -72° C. for 0.5 hour then at 0° C. for 3 hours whereuponit was treated with 95 ml. of water and 5.4 g. of sodium bicarbonate.Work-up with dichloromethane as in Example 1 gave 18 g. of oily productwhich was chromatographed on 180 g. of silica gel. Elution with 19:1parts by volume and 9:1 parts by volume hexane-ether yielded 4.7 g. ofliquid which was fractionated. There was obtained 2.1 g. (53.3%) ofS-(+)-tert. butyl 3-tert. butoxy-2-methylpropionate as a colorlessliquid, b.p. 77°-79.5° C. (10 mm Hg.). [α²⁵ D+19.74° (C 4, CH₃ OH).

EXAMPLE 14 R-(+)-tert. Butoxy-2-methyl-1-propanol

To a stirred slurry of 0.352 g. (9.26 mmoles) of lithium aluminumhydride in 13 ml. of anhydrous ether was added a solution of 1 g. (4.63mmoles) of S-(+)-tert. butyl 3-tert. butoxy-2-methylpropionate in 13 ml.of anhydrous ether, over a 5 min. period, keeping the temperature at5°-10° C. After stirring at room temperature for 3 hours, the reactionmixture was carefully decomposed by the addition of 0.66 ml. of 10%aqueous sodium hydroxide and 0.73 ml. of water with ice bath cooling.Stirring was continued at room temperature for 15 minutes then thesolids were filtered and washed with ether. The filtrate and washes werecombined, washed with brine, dried, filtered and concentrated underreduced pressure. The residue (0.663 g.) was chromatographed on 30 g. ofsilica gel. Elution with 2:1 parts by volume and 1:1 parts by volumehexane-ether yielded a liquid which was evaporatively distilled giving0.526 g. (77.9%) of R-(+)-tert. butoxy-2-methyl-1-propanol as acolorless liquid, b.p. 62°-67° C. (bath temperature) (10 mm Hg.); [α]²⁵D+0.49° (C 4, CH₃ OH).

EXAMPLE 15 R-(+)-4-tert. Butoxy-3-methylbutyronitrile

A solution of 19.3 g. (0.132 mole) of R-(+)-3-tert.butoxy-2-methyl-1-propanol and 38.6 g. (0.147 mole) oftriphenylphosphine in 75 ml. of dichloromethane was stirred with icebath cooling while 24.9 g. (0.14 mole) of N-bromosuccinimide was addedin small portions keeping the temperature below 30° C. The reactionmixture was stirred at room temperature for 1 hour then thedichloromethane was distilled at atmospheric pressure. The bromide wasdistilled from the residue under reduced pressure giving 23.1 g. ofR-(+)-3-tert.-butoxy-2-methyl-1-bromopropane as a colorless liquid, b.p.62°-65° C. (10 mm Hg.). This material was dissolved in 144 ml. ofmethanol and 36 ml. of water and treated with 11.07 g. (0.225 mole) ofsodium cyanide. The resulting mixture was stirred and heated at refluxfor 17 hours, then cooled, diluted with water and worked-up byextraction with dichloromethane and worked up as in Example 1. The crudeproduct (18.9 g.) was chromatographed on 500 g. of silica gel. Elutionwith 9:1 parts by volume and 4:1 parts by volume hexane-ether gave aliquid which was evaporatively distilled yielding R-(+)-4-tert.butoxy-3-methylbutyronitrile as a colorless liquid, b.p. 88°-90° C.(bath temperature) (11 mm Hg.); [α]²⁵ D+7.41° (C 1.8, C₆ H₆).

EXAMPLE 16 R-4-tert. Butoxy-3-methylbutanal

R-4-tert. butoxy-3-methylbutanal was prepared starting fromR-(+)-4-tert. butoxy-3-methylbutyronitrile using the procedure ofExample 6. The crude product was evaporatively distilled giving theR-4-tert. butoxy-3-methylbutanal in 70% yield, as a colorless liquid,b.p. 81°-85° C. (bath temperature (11 mm Hg.).

EXAMPLE 17 Mixture of (2R,4R)- and (2R,4S)-1-tert.Butoxy-2-methylhept-5-yn-4-ol

The mixture of (2R,4R)- and (2R,4S)-1-tert.butoxy-2-methylhept-5-yn-4-ol was prepared from R-4-tert.butoxy-3-methylbutanal using the procedure of Example 7. The mixture of(2R,4R)- and (2R,4S)-1-tert. butoxy-2-methylhept-5-yn-4-ol was obtainedin 83% yield after purification by column chromatography (silica gel;eluted with 2:1 parts by volume and 1:1 parts by volume hexane-ether)and evaporative distillation as a colorless liquid, b.p. 73°-76° C.(bath temperature) (0.1 mm Hg.).

EXAMPLE 18 Mixture of (2R,4R)- and (2R,4S)-Z-1-tert.Butoxy-2-methylhept-5-en-4-ol

The mixture of (2R,4R)- and (2R,4S)-1-tert.butoxy-2-methylhept-5-yn-4-ol was hydrogenated using the proceduredescribed in Example 8. The crude product was evaporatively distilledgiving the mixture of (2R,4R)- and (2R,4S)-Z-1-tert.butoxy-2-methylhept-5-en-4-ol in 90% yield, as a colorless liquid, b.p.74°-76° C. (bath temperature) (0.1 mm Hg).

EXAMPLE 19 Mixture of (3R,7R)- and (3S,7R)-E-Ethyl 8-tert.butoxy-3,7-dimethyl-4-octenoate

Using the procedure of Example 4, the mixture of (2R,4R)- and(2R,4S)-Z-1-tert. butoxy-2-methylhept-5-en-4-ol was converted into themixture of (3R,7R)- and (3S,7R)-E-ethyl 8-tert.butoxy-3,7-dimethyl-4-octenoate in 89% yield after purification of thelatter by column chromatography (silica gel--eluted with 9:1 parts byvolume and 4:1 parts by volume hexane-ether) and evaporativedistillation. The mixture of (3R,7R)- and (3S,7R)-E-ethyl 8-tert.butoxy-3,7-dimethyl-4-octenoate was obtained as a colorless oil, b.p.74°-80° C. (bath temperature) (0.1 mm Hg.); [α]²⁵ D+5.79°. (C2, C₆ H₆).

EXAMPLE 20 Mixture of (3R,7R)- and (3S,7R)-E-8-tert.Butoxy-3,7-dimethyl-4-octen-1-ol

The mixture of (3R,7R)- and (3S,7R)-E-ethyl 8-tert.butoxy-3,7-dimethyl-4-octenoate was reduced using the proceduredescribed in Example 9. The mixture of (3R,7R)- and (3S,7R)-E-8-tert.butoxy-3,7-dimethyl-4-octen-1-ol was obtained in 85% yield afterpurification by column chromatography (silica gel--eluted with 2:1 partsby volume and 1:1 parts by volume hexane-ether) and evaporativedistillation. The product was a colorless oil, b.p. 74°-77° C. (bathtemperature) (0.05 mm Hg.)

EXAMPLE 21 Mixture of (3R,7R)- and (3S,7R)-E-8-tert.Butoxy-3,7-dimethyl-4-octenal

The mixture of (3R,7R)- and (3S,7R)-E-8-tert.butoxy-3,7-dimethyl-4-octen-1-ol was oxidized using the proceduredescribed in Example 10. The mixture of (3R,7R)- and (3S,7R)-E-8-tert.butoxy-3,7-dimethyl-4-octenal was obtained in 87.3% yield afterpurification by evaporative distillation, as a colorless oil, b.p.68°-74° C. (bath temperature) (0.05 mm Hg.).

EXAMPLE 22 Mixture of (2R,6R)- and (2R,6S)-tert. Butyl2,6,10-trimethylundeca-4,8-dien-1-yl ether

The mixture of (2R,6R)- and (2R,6S)-tert. butyl2,6,10-trimethylundeca-4,8-dien-1-yl ether was prepared starting fromthe mixture of (3R,7R)- and (3S,7R)-E-8-tert.butoxy-3,7-dimethyl-4-octenal using the procedure described in Example11. Column chromatography of the crude product (silica gel--eluted with19:1 parts by volume and 9:1 parts by volume hexane-ether) followed byevaporative distillation gave the mixture of (2R,6R)- and (2R,6S)-tert.butyl 2,6,10-trimethylundeca-4,8-dien-1-yl ether in 78% yield, as acolorless oil, b.p. 81°-84° C. (bath temperature) (0.1 mm Hg.); [α]²⁵D+6.85° (C1.78, C₆ H₆).

EXAMPLE 23 Mixture of (2R,6R)- and (2R,6S)-t-Butyl2,6,10-trimethylundec-1-yl ether

A mixture of 0.459 g. (2.1 mmoles) of a mixture of (2R,6R)- and(2R,6S)-tert. butyl 2,6,10-trimethylundeca-4,8-dien-1-yl ether, 0.2 g.of 5% palladium on carbon and 25 ml. of ethyl acetate was stirred in anatmosphere of hydrogen, at room temperature for 4 hours. The catalystwas filtered and the filtrate was concentrated in vacuo. Evaporativedistillation of the residue gave 0.424 g. (91%) of a mixture of (2R,6R)-and (2R,6S)-t-butyl-2,6,10-trimethylundec-1-yl ether as a colorless oil,b.p. 78°-81° C. (bath temperature) (0.06 mm Hg.); [α]²⁵ D+7.02° (C1.37,C₆ H₆).

EXAMPLE 24 Mixture of 2R,6R-2,6,10-Trimethylundecan-1-ol and2R,6S-2,6,10-Trimethylundecan-1-ol

A solution of 0.336 g. (1.24 mmoles) of the mixture of (2R,6R)- and(2R,6S)-t-butyl 2,6,10-trimethylundec-1-yl ether in 7 ml. oftrifluoroacetic acid was kept at 0° C. for 6 hours then poured on iceand the resulting mixture was neutralized with 1 N aqueous sodiumhydroxide. Extraction with ether and work up as in Example 1 gave 0.366g. of yellow oil which was dissolved in 10 ml. of 10% methanolicpotassium hydroxide. After stirring at rom temperature for 1 hour, thesolution was neutralized with 1 N aqueous hydrochloric acid and theorganic materials were isolated by extraction with ether and worked upas in Example 1. The crude product (0.192 g.) was chromatographed on 10g. of silica gel. Elution with 9:1 parts by volume, 4:1 parts by volumeand 2:1 parts by volume hexane-ether yielded the mixture of2R,6R-2,6,10-trimethylundecan-1-ol and2R,6S-2,6,10-trimethylundecan-1-ol which was evaporatively distilledgiving 0.159 g. (60%) of this product as a colorless oil, b.p. 74°-78°C. (bath temperature) (0.1 mm Hg.); [α]²⁵ D+8.42° (C2, hexane).

EXAMPLE 25 rac. 3-Benzyloxy-2-methylpropionitrile

Benzyl alcohol (108 g.; 1 mole) was stirred and treated with 0.3 g. of50% by weight sodium hydride in a mineral oil dispersion. To theresulting solution was added dropwise 415 ml. (335 g.; 5 moles) ofmethacrylonitrile over a 40 minute period, at room temperature. Thereaction mixture was heated at 60°-65° C. for 5 hours then cooled,acidified with 1 N aqueous H₂ SO₄ and diluted with ether. The ethersolution was washed twice with saturated brine then dried, filtered andconcentrated in vacuo. Distillation of the residue gave, after removalof low boiling materials, 149.3 g. (85%) of rac.3-benzyloxy-2-methylpropionitrile as a colorless liquid, b.p. 90°-93° C.(0.02 mm Hg.).

EXAMPLE 26 rac.-Methyl 3-benzyloxy-2-methylpropionate

A solution of 50 g. (0.286 mole) of rac.3-nbenzyloxy-2-methylpropionitrile in 250 ml. of methanol was cooled inan ice-salt bath and stirred while HCl gas was passed in. After thesolution had become saturated with HCl, it was refluxed for 2.25 hoursthen concentrated under reduced pressure (aspirator). The residue wastreated with aqueous K₂ CO₃ and the resulting alkaline mixture wasworked up by ether extraction in the manner of Example 1 giving 52.2 g.of an oil. This material was distilled under reduced pressure yieldingrac.-methyl 3-benzyloxy-2-methylpropionate as a colorless liquid, b.p.88°-90° C. (0.03 mm Hg.).

EXAMPLE 27 rac.-3-benzyloxy-2-methyl-1-propanol

Reduction of the rac.-methyl-3-benzyloxy-2-methylpropionate was carriedout with sodium bis(2-methoxyethoxy)-aluminum hydride using theprocedure described in Example 9. Distillation of the crude productafforded the rac. 3-benzyloxy-2-methyl-1-propanol in 90.5% yield as acolorless liquid, b.p. 94°-98° C. (0.1 mm Hg.).

EXAMPLE 28 rac.-3-Benzyloxy-2-methylpropionic acid

A solution of 3.2 g. (0.0154 mole) ofrac.-methyl-3-benzyloxy-2-methylpropionate in 35 ml. of methanol wasstirred at 0° C. while 15.4 ml. of 1 N aqueous NaOH was added dropwise.The reaction mixture was stirred at 0° C. for 1 hour then at roomtemperature for 2 hours. An additional 1.5 ml. of 1 N aqueous NaOH wasthen added and stirring was continued for 1.5 hour at room temperature.The resulting solution was diluted with water some NaCl was added andthe mixture was extracted with ether. The aqueous solution was acidifiedwith 3 N aqueous HCl and the liberated acid was isolated by etherextraction in the usual manner giving 2.5 g. (84%) ofrac.-3-benzyloxy-2-methylpropionic acid as an oil.

EXAMPLE 29 rac.-3-Hydroxy-2-methylpropionic acid

A mixture of 2 g. (0.0103 mole) of rac.-3-benzyloxy-2-methylpropionicacid, 0.5 g. of 5% palladium on carbon and 20 ml. of anhydroustetrahydrofuran was stirred in atmosphere of hydrogen until 1 moleequivalent of hydrogen was taken up. The catalyst was filtered andwashed with CH₂ Cl₂ then the filtrate and washes were combined andconcentrated under reduced pressure. The residue was evaporativelydistilled giving 0.88 g. (82%) of rac.-3-hydroxy-2-methylpropionic acidas a viscous, colorless oil, b.p. 105°-110° C. (bath temperature) (0.275mm Hg.).

EXAMPLE 30 rac. Methyl 3-hydroxy-2-methylpropionate

A solution of 5 g. (0.024 mole) of rac.-methyl3-benzyloxy-2-methylpropionate in 50 ml. of ethyl acetate was treatedwith 0.5 g. of 5% by weight palladium on 95% by weight carbon andstirred in an atmosphere of hydrogen. When hydrogen uptake ceased, thecatalyst was filtered and washed with ethyl acetate then the filtrateand washes were combined and concentrated under reduced pressure. Theresidue was evaporatively distilled giving 2.1 g. (74%) of rac. methyl3-hydroxy-2-methylpropionate as a colorless liquid, b.p. 74°-78° C.(bath temperature) (11 mm Hg.).

EXAMPLE 31 rac.-tert. Butyl 3-tert. butoxy-2-methylpropionate

Treatment of rac.-3-hydroxy-2-methylpropionic acid with isobutyleneusing the procedure of Example 13 gave the rac.-tert. butyl 3-tert.butoxy-2-methylpropionate in 81.2% yield as a colorless liquid, b.p.81°-87° C. (bath temperature) (10 mm Hg.).

EXAMPLE 32 rac.-Methyl 3-tert. butoxy-2-methylpropionate

Treatment of hydroxy ester rac. methyl 3-hydroxy-2-methylpropionate withisobutylene using the procedure described in Example 13 gave rac.-methyl3-tert. butoxy-2-methylpropionate in 43.5% yield as a colorless liquid,b.p. 75°-85° C. (bath temperature) (11 mm Hg.).

EXAMPLE 33 rac.-3-tert. butoxy-2-methyl-1-propanol

Reduction of rac.-tert. butyl 3-tert. butoxy-2-methylpropionate wascarried out with lithium aluminum hydride using the procedure describedin Example 14. The resulting hydroxy ether, rac.-3-tert.butoxy-2-methyl-1-propanol was obtained in 88% yield as a colorlessliquid, b.p. 70°-72° C. (10 mm Hg.).

EXAMPLE 34 rac.-3-tert. Butoxy-2-methyl-1-propanol

Reduction of the ester rac.-methyl 3-tert. butoxy-2-methylpropionate wascarried out with lithium aluminum hydride using the procedure describedin Example 14. The hydroxy ether, rac-3-tert. butoxy-2-methyl-1-propanolwas obtained in 94.2% yield as a colorless liquid, b.p. 70°-80° C. (bathtemperature) (10 mm Hg.).

EXAMPLE 35 rac.-3-tert. butoxy-2-methyl-1-bromopropane

Reaction of rac.-3-tert. butoxy-2-methyl-1-propanol withbromine-triphenylphosphine using the procedure of Example 2 gaverac.-3-tert. butoxy-2-methyl-1-bromopropane as a colorless liquid, b.p.67°-77° C. (bath temperature) (9 mm Hg.).

EXAMPLE 36 Separation of (2R,4R)- and (2R,4S)-1-tert.butoxy-2-methylhept-5-yn-4-ol

A 9.5 g. sample of the Mixture of (2R,4R)- and (2R,4S)-1-tert.butoxy-2-methylhept-5-yn-4-ol prepared as in Example 17 (approximately1:1) was separated by preparative high pressure liquid chromatography. A4 ft.×21 mm. (i.d.) column of silica gel (20-44μ) was employed with acarrier solvent of 10:1 heptane-ethyl acetate at a flow rate of 40ml/min and a pressure drop across the column of 800 psi, at roomtemperature. The sample was injected in 1.5 g. portions. The less polar(4S)-epimer was isolated after one pass (3.55 g.) and was found to be90% pure (gc). A 0.208 g. sample of this material was further purifiedby dissolution in ether and stirring at room temperature for 3.5 hourwith 10 % aqueous silver nitrate solution. The ether solution wasseparated and processed in the usual manner, then the residue wasevaporatively distilled giving pure (2R,4S)-1 -tert.butoxy-2-methylhept-5-yn-4-ol (0.189 g.) as a colorless oil, b.p.88°-94° C. (bath temperature) (0.15 mm Hg.); [α]_(D) ²⁵ -3.10° (c2,CHCl₃).

The more polar (4R)-epimer required 3 passes after which there wasobtained 2.71 g. Evaporative distillation gave (2R,4R)-1-tert.butoxy-2-methylhept-5-yn-4-ol as a colorless liquid, b.p. 64°-67° C.(bath temperature) (0.02 mm Hg.).

EXAMPLE 37 (2R,4S)-Z-1-tert. Butoxy-2-methylhept-5-en-4-ol

A 1.04 g (5.26 mmoles) sample of pure (2R,4S)-1-tert.butoxy-2-methylhept-5-yn-4-ol was hydrogenated using the proceduredescribed in Examples 8 and 18. There was obtained (2R,4S)-Z-1-tert.butoxy-2-methylhept-5-en-4-ol as a colorless oil, b.p. 86°-89° C. (bathtemperature) (0.15 mm Hg.); [α]_(D) ²⁵ -10.99° (c2, CHCl₃).

EXAMPLE 38 (3R,7R)-E-Ethyl 8-tert. butoxy-3,7-dimethyl-4-octenoate

Using the procedure of Examples 4 and 19, (2R,4S)-Z-1-tert.butoxy-2-methylhept-5-en-4-ol was converted into (3R,7R)-E-ethyl 8-tert.butoxy-3,7-dimethyl-4-octenoate which was isolated in 82% yield as acolorless oil, b.p. 74°-78° C. (bath temperature) (0.2 mm Hg.) afterevaporative distillation.

EXAMPLE 39

By the procedures of Examples 9, 10, 11, 23 and 24, 3R,7R-E-ethyl8-tert. butoxy-3,7-dimethyl-4-octenoate is converted to2R,6R-2,6,10-trimethylundecan-1-ol via the following intermediates:

3R,7R-E-8-tert. butoxy-3,7-dimethyl-4-octen-1ol;

3R,7R-E-8-tert. butoxy-3,7-dimethyl-4-octenal;

2R,6R-tert. butyl 2,6,10-trimethyl-undeca-4,8-dien-1yl ether; and

2R,6R-t-butyl 2,6,10-trimethylundec-1-yl ether.

EXAMPLE 40 (3S,7R)-Ethyl-8-tert. butoxy-3,7-dimethyloctanoate

A mixture of 1.104 g. (4.084 mmoles) of (3R,7R)-E-Ethyl 8-tert.butoxy-3,7-dimethyl-4-octenoate, a small amount of Raney nickel, and 30ml. of ethyl acetate was stirred in an atmosphere of hydrogen, at roomtemperature, for 2 hours during which time approximately one equivalentof hydrogen was taken up. The catalyst was filtered off and washed withethyl acetate. Concentration of the combined filtrate and washes invacuo followed by evaporative distillation afforded 1.045 g. (95%) ofsaturated ester (3S,7R)-Ethyl 8-tert. butoxy-3,7-dimethyloctanoate as acolorless oil, b.p. 80°-83° C. (bath temperature) (0.15 mm Hg.).

EXAMPLE 41 (3S,7R)-8-tert. Butoxy-3,7-dimethyloctanoic Acid

A solution of 0.108 g. (0.397 mmoles) of (3S,7R)-Ethyl 8-tert.butoxy-3,7-dimethyloctanoate in 2.5 ml. of methanol and 1.5 ml. of 6 Naqueous NaOH was refluxed for 3 hours. The resulting solution wascooled, diluted with water and extracted with diethyl ether. (The etherextract was discarded). The aqueous solution was then acidified with 6 Naqueous HCl and extracted with diethyl ether. The combined etherextracts were washed with water and brine, then dried over anhydrousMgSO₄, filtered and concentrated under reduced pressure yielding 0.082g. of the oily acid (3S,7R)-8-tert. Butoxy-3,7-dimethyloctanoic acid[α]²⁵ D+4.26° (c 2, benzene).

EXAMPLE 42 (3S,7R)-8-tert. Butoxy-3,7-dimethyl-1-octanol

A slurry of 125 mg. (3.28 mmoles) of lithium aluminum hydride in 25 ml.of ether was stirred and cooled in an ice bath while a solution of 893mg. (3.28 mmoles) of (3S,7R)-Ethyl 8-tert. butoxy-3,7-dimethyloctanoateabove, in 25 ml. of ether was added dropwise. After the addition wascomplete, the reaction mixture was stirred at room temperature for 4hours then cooled to 0° C. and cautiously decomposed with 0.45 ml. ofsaturated aqueous sodium sulfate solution. After stirring at roomtemperature for 19 hours, the mixture was filtered and the filtrate wasconcentrated under reduced pressure. The crude product (686 mg) waschromatographed on 30 g. of silica gel. Elution with 2:1 and 1:1 partsby volume hexane-ether gave 669 mg. (89%) of (3S,7R)-8-tert.Butoxy-3,7-dimethyl-1-octanol.

EXAMPLE 43 (3S,7R)-8-tert. Butoxy-3,7-dimethyl-1-octanolp-toluenesulfonate

To a stirred solution of 640 mg. (2.78 mmoles) of (3S,7R)-8-tert.Butoxy-3,7-dimethyl-1-octanol in 12 ml. of pyridine at 0° C. was added1.057 g. (5.56 mmoles) of p-toluenesulfonyl chloride. The resultingmixture was kept at 0° C. for 17 hours, then treated with ice-water andstirred for 30 minutes. The precipiated oil was extracted with diethylether and the ether extracts were washed with cold 1 N aqueous HCl,saturated aqueous NaHCO₃, water, and saturated brine then dried overanhydrous MgSO₄. Filtration and solvent removal in vacuo afforded 1.017g. (95%) of the (3S,7R)-8-tert. Butoxy-3,7-dimethyl-1-octanolp-toluenesulfonate as a yellow oil.

EXAMPLE 44 (2R,6R)-tert.-Butyl 2,6,10-trimethylundec-1-yl ether

To a stirring and refluxing slurry of 432 mg. (18 mmoles) of magnesiumpowder in 1 ml. of anhydrous tetrahydrofuran was added a crystal ofiodine followed by a few drops of a solution of 2.057 g. (15 mmoles) of1-bromo-2-methylpropane in 12 ml. of tetrahydrofuran. After the reactionhad begun, the remainder of the bromide solution was added dropwise andwhen the addition was complete, the mixture was stirred under reflux for1 hour then cooled to room temperature. A solution of 437 mg. (1.14mmoles) of (3S,7R)-8-tert. Butoxy-3,7-dimethyl-1-octanolp-toluenesulfonate in 2.5 ml. of tetrahydrofuran was stirred at -78° C.while 1.42 ml. (1.42 mmoles) of the above Grignard solution was addeddropwise followed by 0.058 ml. of 0.1 M dilithium tetrachlorocupratesolution in tetrahydrofuran. The resulting mixture was stirred at -78°C. for 10 minutes, then allowed to warm to room temperature over a 2hour period and stirred for an additional 18 hours. Upon treatment with1 N aqueous H₂ SO₄, the organic materials were extracted with ether. Theether extracts were washed with water, saturated aqueous NaHCO₃ andsaturated brine, combined and dried over anhydrous MgSO₄. Filtration andconcentration under reduced pressure gave 339 mg. of crude product whichwas chromatographed on 15 g. of siliva gel. Elution with 19:1 and 9:1parts by volume hexane/ether afforded 237 mg. of (2R,6R)-tert.-Butyl2,6,10-trimethylundec-1-yl ether containing about 20% of (3S,7R)-8-tert.butoxy-3,7-dimethyl-1-bromo-octane as an impurity. This material wasused for cleavage to the alcohol without further purification.

EXAMPLE 45 (2R,6R)-2,6,10-Trimethylundecan-1-ol

The crude ether (2R,6R)-tert.-Butyl 2,6,10-trimethylundec-1-yl ether(237 mg), at 0° C. was stirred and treated with 4 ml. of trifluoroaceticacid. The resulting solution was kept at 0° C. for 17 hours after whichtime the trifluoroacetic acid was evaporated at reduced pressure. Theresidue was made alkaline with 20% by weight methanolic KOH thenneutralized with 6 N aqueous HCl. The product was isolated by etherextraction in the usual manner giving 181 mg. of silica gel. Elutionwith 7:3 and 6:4 parts by volume hexane/ether gave 130 mg. (53.3% basedon tosylate (3S,7R)-8-tert. Butoxy-3,7-dimethyl-1-octanolp-toluenesulfonate) of pure alcohol (2R,6R)-2,6,10-trimethylundecan-1-olas a colorless oil; [α]²⁵ D+8.15° (c 2, hexane).

We claim:
 1. A compound of the formula: ##STR42## wherein R₂ is t-butyl,tetrahydropyranyl, benzyl, benzhydryl, trityl, methoxymethyl, dimethylt-butylsilyl.
 2. The compound of claim 1 wherein said compound is(2R,4R)-1-tert.-butoxy-2-methylhept-5-yn-4-ol.
 3. The compound of claim1 wherein said compound is rac. 1-benzyloxy-2-methylhept-5-yn-4-ol.
 4. Acompound of the formula: ##STR43## wherein R₂ is t-butyl,tetrahydropyranyl, benzyl, benzhydryl, trityl, methoxymethyl, dimethylt-butylsilyl.
 5. The compound of claim 4 wherein said compound is rac.E-1-benzyloxy-2-methyl-5-hepten-4-ol.
 6. The compound of claim 4 whereinsaid compound has the formula: ##STR44## wherein R₂ is as above, and Δdenotes a cis configuration across the double bond.
 7. The compound ofclaim 4 wherein said compound has the formula: ##STR45## wherein R₂ isas above; and Δ' denotes a trans configuration across the double bond.